It has been shown in our laboratory and those of others that the Auger effect accompanying 125I decay is extremely toxic when 125I is incorporated into cellular DNA in the form of iododeoxyuridine (125IUdR). We now propose to use the established cell culture test system to compare the toxicity of 125I attached to intercalating agents with that of 125I covalently bound to DNA. Alternatively, the toxicity of 125I-labeled estrogens and antiestrogens bound to nuclear receptors will be determined. In addition, the toxicity of other Auger electron-emitting radionuclides (including 57Co, 75Se, 99mTc, 111In, 113mIn and 201Tl), the alpha emitter astatine-211, and selected positron emitters, will be tested in the same system and compared with that of 125I. The intracellular distribution of various compounds labeled with these nuclides will be measured and its relationship to their biological consequences determined. This information will be used to establish the potential biohazards or therapeutic benefits of some of the compounds. The therapeutic efficacy of such compounds will be further examined and compared with 125IUdR in the mouse ascites tumor model previously established in this laboratory. We also propose to investigate the mechanisms and various aspects by which Auger effect causes biological damages. First, relative sensitivities of various cell lines to Auger electrons and low LET radiations will be compared and the differences related to their variations in nuclear size, DNA content, chromosome number and the cellular ability to repair single-strand breaks. Secondly, cytogenetic changes will be scored in cell cultures exposed to Auger and alpha emitters and the results interpreted in relation to their lethal effects. Lastly, an electron spin resonance study of 125IUdR will be initiated to elucidate the action of Auger electrons at the molecular level.